Pyroptosis mediated renal injury caused by chronic intermittent hypoxia and the intervention effect of edaravone in rats / 中国临床药理学与治疗学

ABSTRACT

AIM: To study the protective effect of edaravone on renal injury induced by chronic intermittent hypoxia and its effect on Caspase-1 mediated pyroptosis signaling pathway in rats. METHODS: Twenty four SPF male SD rats were randomly divided into normal control group, intermittent hypoxia group, intermittent hypoxia + normal saline group and intermittent hypoxia + edaravone group, with 6 rats in each group. The four groups of rats were placed in the closed feeding chamber for modeling. The oxygen concentration in the NC group was maintained at about 21%; the IH group, IH + NS group and IH + EDA group were given regular input of pure oxygen, pure nitrogen and compressed air to form anoxic-reoxygenation cycle (60 s hypoxic period + 60 s reoxygenation period). During the hypoxic period, the oxygen concentration in the chamber was reduced to 6%-7%, and the rats in the IH + EDA group were intraperitoneally injected with edaravone at a dose of 5 mg/kg per day before modeling, while the rats in the IH + NS group were intraperitoneally injected with normal saline at the same dose per day. After 8 weeks of modeling, blood and kidney tissue samples were collected to measure the levels of Crea and Urea in each group. The pathological changes and fibrosis degree of kidney were observed under light microscope after HE and Masson staining. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) were determined by chemical method. The expression levels of NLRP3, Caspase-1 and IL-1β in renal tissues were determined by immunohistochemical staining. The expression levels of caspase-1 and IL-1β in renal tissues were determined by Western blot. GSDMD and IL-18 mRNA were detected by RT-PCR. RESULTS: After intermittent hypoxia exposure, serum Crea and Urea were increased significantly (P < 0.01), renal tubules were damaged by pathology, collagen fiber deposition occurred in balloon space of renal units, MDA content was increased and SOD activity was decreased (P < 0.01). Caspase-1, NLRP3, IL-1β protein expression increased (P < 0.01 or P < 0.05), GSDMD mRNA and IL-18 mRNA amplification increased (P < 0.01); After Edaravone intervention, the above indexes showed a reverse trend compared with that after intermittent hypoxia exposure, and the pathological damage of kidney was reduced (P < 0.01 or P < 0.05). CONCLUSION: Chronic intermittent hypoxia may mediate kidney injury through oxidative stress activation of caspase-1 involved in the cell pyroptosis signaling pathway, while edaravone may inhibit the activation of pyroptosis signaling pathway by scavenging oxygen free radicals and down-regulating the level of oxidative stress in the body, thus playing a protective role in kidney.